Cerebrovascular deposition of the amyloid [unreadable]-protein (A[unreadable]), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease (AD) and several related hereditary cerebral hemorrhage with amyloidosis (HCHWA) disorders. A[unreadable] is proteolytically derived from its parent molecule the amyloid [unreadable]-protein precursor (A[unreadable]PP). Apolipoprotein E (ApoE) genotype can facilitate both cerebrovascular A[unreadable] deposition and hemorrhagic stroke. It is significant that CAA accounts for up to 20% of cases of spontaneous primary intracerebral hemorrhage. Moreover, CAA is most severe in HCHWA patients often resulting in early recurrent and fatal intracerebral hemorrhages. The reason as to why there is preferential cerebrovascular A[unreadable] deposition in HCHWA disorders leading to hemorrhagic stroke and how ApoE may facilitate these pathological processes remains unresolved. [unreadable] [unreadable] We have shown that certain HCHWA mutant forms of A[unreadable], which exhibit a loss or change in charge at peptide residues 22 or 23, possess enhanced pathogenic properties towards cultured cerebrovascular cells. In addition, ApoE genotype can further influence the pathogenic effects of A[unreadable] in these in vitro paradigms. However, many of these issues can be better studied in valid in vivo models for CAA. Therefore, the overall hypotheses that forms the basis of this proposal is that expression of HCHWA mutant A[unreadable]PP in transgenic mice will lead to the preferential development of CAA and human ApoE genotype can further influence this pathology and promote cerebral hemorrhage. The broad objectives of this proposal are two-fold. First, we will compare the pathological consequences of neuronal over-expression of several human A[unreadable]PP forms yielding either wild-type or CAA mutant A[unreadable] with regards to the development of CAA. The CAA mutant forms A[unreadable]PP will contain either a single Dutch E22Q AB substitution or double Dutch/Iowa E22Q,D23N A[unreadable] substitutions. Second, the influence of human ApoE genotype on A[unreadable] deposition, the development of CAA, and cerebral hemorrhage will be investigated in these in vivo models. These proposed studies stem from our overall focus and continuing work on investigating the role of ABPP and its derived fragment A6 in the development of CAA, loss of vessel wall integrity, and hemorrhagic stroke. Completion of these specific aims will produce valuable models for both the further study of pathogenic mechanisms in CAA and in vivo systems to develop and test therapeutic strategies to mitigate cerebrovascular A[unreadable] deposition and the subsequent pathological consequence of hemorrhagic stroke. [unreadable] [unreadable]